The high fatality and disability rate of atrial fibrillation (AF) strongly promote the development of pathogenesis and treatment of AF that is of great value. The present research attempted to clarify potential mechanisms of Mujiangzi oil (CV-3) in treating AF by constructing an AF cardiomyocytes model and using a network pharmacology approach. The experiment was divided into 4 groups: control, an AF model, AF + CV-3-treated, and the AF + verapamil group. Flow cytometry and the MTT assay were employed to detect cell apoptosis and cell viability, respectively. The main active components of CV-3 and predicted targets were obtained firstly, and molecular docking was performed. In the AF model, the cell apoptosis was aggravated, but inhibited in the CV-3-treated group. In addition, the cell viability was recovered after CV-3 treatment compared with the model group. Five potential active compounds of CV-3 were collected, including effective ingredients N-decanoic acid, spathulenol, copaene, β-panasinsene, and eucalyptol. Among them, N-decanoic acid and spathulenol was demonstrated to bind to PTGS2 with binding energy of −4.08 and −7.09 kcal/mol, respectively, and hydrogen bonds interaction were found. The present study indicated that CV-3 could alleviate AF cardiomyocytes apoptosis and improve cardiomyocytes viability, and N-decanoic acid and spathulenol may be the key components of CV-3 in treatment of AF by regulating PTGS2. This study provided the possible target PTGS2 and the understanding of molecular mechanisms of CV-3 in treating AF.